Carbamazepine - instructions for use, dose, side effects, contraindications

Sunauxiliaries: starch potato - 80.0 mg, silicon dioxide colloid (aerosil) - 16.4 mg, povidone low molecular weight (polyvinylpyrrolidone low molecular weight medical) - 14.0 mg, polysorbate 80 (tween 80) 3.2 mg, talcum powder - 3.2 mg, magnesium stearate - 3.2 mg.

Description:

Tablets are white or white with a yellowish tint of color, flat-cylindrical, with a facet and a risk.

Pharmacotherapeutic group:Antiepileptic remedy

ATX: & nbsp

N.03.A.F.01 Carbamazepine

Pharmacodynamics:

Carbamazepine is a dibenzoazepine derivative. Along with antiepileptic, the drug also has neurotropic and psychotropic effects.

The mechanism of action of carbamazepine is currently only partially explained. Carbamazepine stabilizes membranes of overexcited neurons, suppresses serial discharges of neurons and reduces the synaptic transmission of exciting impulses.Probably the main mechanism of action of carbamazepine is the prevention of repeated occurrence in the depolarized neurons of sodium-dependent action potentials due to the blockade of "action" -dependent and potential-dependent sodium channels.

When used as a monotherapy in patients with epilepsy (especially in children and adolescents), the psychotropic effect of the drug was noted, which included a positive effect on the symptoms of anxiety and depression, as well as a decrease in irritability and aggressiveness. There is no unambiguous data on the effect of the drug on cognitive and psychomotor functions: in some studies, a double or negative effect was shown that depended on the dose of the drug, in other studies, the positive effect of the drug on attention and memory was revealed.

how neurotrophic agent the drug is effective in a number of neurological diseases. So, for example, with idiopathic and secondary neuralgia of the trigeminal nerve, he prevents the occurrence of paroxysmal pain attacks.

With alcohol withdrawal syndrome, the drug raises the threshold of convulsive readiness,which in this state is usually reduced, and reduces the severity of clinical manifestations of the syndrome, such as increased excitability, tremor, gait disturbance.

In patients with diabetes insipidus, the drug reduces diuresis and thirst.

how psychotropic drug the drug is effective in affective disorders, namely, in the treatment of acute manic conditions, with the supportive treatment of bipolar affective (manic-depressive) disorders (either as monotherapy or in combination with antipsychotic drugs, antidepressants or lithium preparations), with attacks of schizoaffective psychosis , with manic attacks, where it is used in combination with neuroleptics, as well as with manic-depressive psychosis with fast cycles. The ability of the drug to suppress manic manifestations may be due to the inhibition of the exchange of dopamine and norepinephrine.

Pharmacokinetics:

Suction

After oral administration carbamazepine absorbed almost completely, when taking a tablet form, absorption is relatively slow. After a single pill Carbamazepine mean maximum concentration C_maxachieved after 12 hours. After a single oral intake of the tablet Carbamazepine 400 mg, the average value of C_max the unchanged active substance is about 4.5 μg / ml.

When using carbamazepine tablets, eating does not significantly affect the speed and degree of absorption of the drug.

The equilibrium concentration of carbamazepine in plasma is reached within 1-2 weeks. The time to achieve individual and depends on the degree of auto-induction of liver enzyme systems carbamazepine, geteroinduktsii other simultaneously applicable medicaments as well as the patient's condition to the purpose of therapy, the dose and duration of treatment. There are significant interindividual differences in the values of equilibrium concentrations in the therapeutic range: in most patients these values range from 4 to 12 μg / ml (17-50 μmol / l).

Distribution and binding to blood plasma proteins

The binding of carbamazepine to plasma proteins is 70-80%. The concentration of unchanged carbamazepine in the cerebrospinal fluid and saliva proportional to the fraction of active substances not bound to plasma proteins (20-30%).The concentration of carbamazepine in breast milk is 25-60% of its level in the blood plasma.

Carbamazepine penetrates the placental barrier. Given the complete absorption of carbamazepine, the apparent volume of distribution is 0.8-1.9 l / kg.

Metabolism

Carbamazepine is metabolized in the liver. The main pathway of biotransformation is epoxidation, resulting in the formation of the main metabolites: 10,11 -transdiol derivative and its conjugate with glucuronic acid. The transformation of carbamazepine-10,11-epoxide into carbamazepine-10,11-trans-diol in the human body takes place using a microsomal enzyme of epoxide hydrolase. The content of carbamazepine-10,11-epoxide (active metabolite) is about 30% of the concentration of carbamazepine in plasma. The main isoenzyme, providing biotransformation of carbamazepine in carbamazepine-10,11-epoxide. Is cytochrome P4503A4. As a result of these metabolic reactions, a small amount of another metabolite, 9-hydroxy-methyl-10-carbamoylacridan, is also formed.

Another important pathway for the metabolism of carbamazepine is the formation, under the influence of the isoenzyme UGT2B7, of various monohydroxylated derivatives, as well as N-glucuronides.

Excretion

The half-life of unchanged carbamazepine after a single oral intake is approximately 36 hours on average, and after repeated administration of the drug - an average of 16-24 hours, depending on the duration of treatment (due to autoinduction of the monooxygenase system of the liver). It was shown that in patients taking simultaneously other drugs inducing liver enzymes (for example, phenytoin, phenobarbital), the half-life of carbamazepine averages 9-10 hours.

When administered carbamazepine-10,11-epoxide, the average half-life of it is about 6 hours.

After a single oral intake of 400 mg of carbamazepine, 72% of the dose taken is excreted in the urine and 28% with feces. About 2% of the dose is taken with urine in the form of unchanged carbamazepine, about 1% - in the form of a pharmacologically active 10,11-epoxide metabolite. After a single oral intake, 30% of carbamazepine is excreted in the urine as final products of epoxidation.

Peculiarities of pharmacokinetics in individual patient groups

Children, due to the faster elimination of carbamazepine, may require the use of higher doses of the drug per kg body weight, compared with adults.

There is no evidence to suggest that the pharmacokinetics of carbamazepine change in elderly patients (compared to older adults).

Data on the pharmacokinetics of carbamazepine in patients with impaired renal or hepatic function have not been reported to date.

Indications:

Epilepsy:

- complex or simple partial epileptic seizures (with or without loss of consciousness) with secondary generalization or without it;

- generalized tonic-clonic epileptic seizures;

- Mixed forms of epileptic seizures.

Carbamazepine, as a rule, is ineffective in absences and myoclonus-epilepsy.

Acute manic conditions and maintenance therapy of bipolar affective disorders with the aim of preventing exacerbations or alleviating clinical manifestations of exacerbation.

Alcohol withdrawal syndrome.

Idiopathic neuralgia of the trigeminal nerve and trigeminal neuralgia in multiple sclerosis (typical and atypical).

Idiopathic neuralgia of the glossopharyngeal nerve.

Contraindications:

- Hypersensitivity to carbamazepine or chemically similar medicinal products (eg, tricyclic antidepressants) or to any other component of the drug;

- atrioventricular block;

- presence in the anamnesis of episodes of oppression of bone marrow hematopoiesis;

- hepatic porphyria (for example, acute intermittent porphyria, late cutaneous porphyria, variegate porphyria);

- use in combination with monoamine oxidase inhibitors (structural similarity with tricyclic antidepressants);

- Children's age up to 4 years.

Carefully:

In those cases when low levels of white blood cells or platelets are observed during treatment (or a tendency to decrease them), you should carefully monitor the patient's condition and the indicators of the developed clinical blood test. If signs of significant bone marrow suppression are revealed, Carbamazepine should be canceled.

Care should be taken when using the drug in patients with hyponatremia of dilution, hypothyroidism.

Carbamazepine should be immediately withdrawn if signs and symptoms are suspected to indicate the development of severe dermatological reactions - for example, Stevens-Johnson syndrome or Lyell's syndrome.

Caution should be used when using carbamazepine in patients with mixedforms of epileptic seizures, including absences (typical or atypical), because of the possible intensification of seizures. If this happens, Carbamazepine should be canceled.

Patients who have a history of heart disease (including decompensated chronic heart failure), liver (including liver failure), kidney (including renal failure), adverse hematologic responses to other drugs, or the abolition of previous treatment with carbamazepine, the drug should appoint only after a careful analysis of the relationship between the expected effect of treatment and the possible risk of therapy, and with careful and regular treatment Rola.

Given the drug interactions and the different pharmacokinetics of antiepileptic drugs, elderly patients of the dose of carbamazepine should be selected with caution.

In the case of development of symptoms and symptoms of hypersensitivity to carbamazepine, the drug should be immediately discontinued.

Given the weak m-cholinoblocking activity of the drug,Care should be taken when prescribing carbamazepine to patients with increased intraocular pressure and prostatic hyperplasia.

Pregnancy and lactation:

It is known that children born to mothers suffering from epilepsy are more likely than others to be prone to intra-uterine development disorders, including developmental malformations. It was reported that carbamazepine, as of all major antiepileptic drugs, is capable of increasing the risk of these disorders, although the final confirmation of this, which would have been obtained as a result of controlled studies using Carbamazepine as a monotherapy to date is not available.

There are reports of cases of congenital diseases and malformations, including the absence of vertebral arches (spina bifida) and other congenital anomalies: defects in craniofacial structures, cardiovascular and other organ systems, hypospadias.

Use with caution the drug Carbamazepine in pregnant women with epilepsy.

In the event that a woman receiving Carbamazepine, has become pregnant or is planning to become pregnant, or if it is necessary to prescribe carbamazepine in pregnancy, should be carefully compared the expected effect of therapy and possible complications, especially in the first 3 months of pregnancy.

With sufficient clinical efficacy for women of childbearing period Carbamazepine should be prescribed as a monotherapy, as the frequency of development of congenital anomalies of the fetus with the use of combined antiepileptic therapy is higher than with the appointment of drugs as monotherapy.

Should be appointed Carbamazepine in the minimum effective dose. It is recommended to regularly monitor the concentration of active substance in the blood plasma.

Patients should be provided with information on the possibility of increasing the risk of malformations and the ability to undergo antenatal diagnostics.

During pregnancy, effective antiepileptic treatment should not be discontinued, as the progression of the disease can have a negative effect on the mother and on the fetus.

It is known that a deficiency of folic acid develops during pregnancy. It has been reported that antiepileptic drugs increase this deficit. This can contribute to an increase in the frequency of birth defects in children born to women,taking antiepileptic drugs. Therefore, before and during pregnancy, an additional intake of folic acid is recommended.

In order to prevent increased bleeding in newborns, women in the last weeks of pregnancy, as well as newborns, are recommended to prescribe a vitamin K₁.

Several cases of epileptic seizures and / or respiratory depression in newborns whose mothers were taken concomitantly with other anticonvulsants have been described. In addition, several cases of vomiting, diarrhea, and / or reduced diets were reported in neonates whose mothers received Carbamazepine. Perhaps these reactions are manifestations in newborn withdrawal syndrome.

Carbamazepine penetrates into breast milk, the concentration in it is 25-60% of the level in the blood plasma. Therefore, the benefits and possible undesirable consequences of breastfeeding should be compared with the ongoing therapy with carbamazepine. Mothers taking the drug may breastfeed their babies, but on condition that the child is monitored for the development of possible adverse reactions (eg, severe drowsiness, allergic skin reactions).

Dosing and Administration:

Inside.The drug can be taken during meals, after meals or in between meals. Tablets should be taken with a small amount of liquid.

The drug can be used as a monotherapy or as part of a combination therapy.

Epilepsy

If possible, the drug should be used as a monotherapy.

The drug is not used for small seizures (petit mal, absance) and myoclonic seizures.

Treatment begins with a small daily dose, which is then slowly increased until an optimal effect is achieved. The dose of carbamazepine is selected individually to achieve adequate control of convulsions.

To determine the optimal dose of the drug, it is recommended to determine the concentration of the active substance in the blood plasma.

When the preparation is added Carbamazepine to other antiepileptic drugs taken dose of the drug Carbamazepine increase gradually. If necessary, appropriate correction of the doses taken.

The initial dose of carbamazepine for adults is 100-200 mg 1 or 2 times a day. Then the dose is slowly increased until the optimal therapeutic effect is achieved; it is usually achieved at a dose of 400 mg 2-3 times a day.Some patients may require an increase in the daily dose to 1600 mg or 2000 mg.

Neuralgia of the trigeminal nerve

Initial dose for adults is 200-400 mg per day. It is slowly increased until the pain disappears (usually up to a dose of 200 mg 3-4 times a day). Then the dose is gradually reduced to the minimum maintenance level. The recommended starting dose for elderly patients is 100 mg twice a day.

Alcohol withdrawal syndrome

The average dose is 200 mg 3 times a day. In severe cases, during the first few days the dose may be increased (for example, to a dose of 400 mg 3 times per day).

In severe manifestations of alcohol abstinence treatment begins with the use of the drug in combination with drugs that have sedative and hypnotic effects (eg, clomethiazole, chlordiazepoxide). After resolving the acute phase, treatment with the drug can be continued as a monotherapy.

Acute manic conditions and maintenance treatment of affective (bipolar) disorders

The daily dose is 400-1600 mg.

The average daily dose is 400-600 mg (in 2-3 doses). In acute manic state, the dose should be increased rather quickly.With maintenance therapy for bipolar disorders, in order to ensure optimal tolerability, each next dose increase should be small, the daily dose increases gradually.

Discontinuation of the drug

Sudden discontinuation may cause epileptic seizures, so carbamazepine should be lifted gradually over 6 months or more. If it is necessary to quickly cancel a drug in a patient with epilepsy, the transition to another antiepileptic agent should be carried out under the cover of the drug shown in such cases.

Use in children

The main indication for the use of the drug Carbamazepine in children - epilepsy. This drug form of the drug should be used to treat the same as in adults, forms of epilepsy in children older than 4 years. Treatment can be started with a dose of 100 mg / day; dose increase gradually, no more than 100 mg per week.

Children aged 4 years and younger are recommended to take the drug Carbamazepine in the form of other medicinal forms (syrup). The initial dose for children aged 4 years and younger is 20-60 mg per day with a gradual increase of 20-60 mg / day every other day.

Maintenance doses: for children set at the rate of 10-20 mg / kg body weight per day (in several receptions).

Age of child	Daily dose
4-5 years	200-400 mg / day
6-10 years	400-600 mg / day
11-15 years old	600-1000 mg / day

As for the use of the drug for other indications, the children have sufficient reliable information, the dosage regimen of the drug is recommended to be selected in accordance with the age and weight of the child, not exceeding the dosages indicated in the table.

Side effects:

Certain types of unwanted reactions, for example, from the side of the CNS (dizziness, headache, ataxia, drowsiness, fatigue, diplopia), from the digestive system (nausea, vomiting), as well as allergic skin reactions, occur very often or often, especially in the beginning of treatment with the drug, or with an excessively high initial dose of the drug or in the treatment of elderly patients.

Dose-dependent adverse reactions usually occur within a few days, both spontaneously and after a temporary dose reduction. The development of adverse reactions from the CNS may be due to a relative overdose of the drug or significant fluctuations in the concentration of the active substance in the blood plasma.In such cases it is recommended to monitor the concentration of active substance in the blood plasma.

When assessing the incidence of various adverse reactions, the following grades are used: "very often" ≥1 / 10, "often" - ≥1 / 100 - <1/10, "sometimes" - ≥1 / 1000 - <1/100 "rarely" - ≥1 / 10,000 - <1/1000, "very rarely "- <1/10 000, including individual reports.

Mental disorders: rarely - hallucinations (visual or auditory), depression, anxiety, aggression, agitation, disorientation; very rarely - activation of psychosis.

From the nervous system: very often - dizziness, ataxia, drowsiness, a sense of fatigue; often - headache, diplopia, impaired vision accommodation (eg, blurred vision); sometimes - abnormal involuntary movements (eg, tremor, "fluttering" tremor /asterixis/, muscular dystonia, tics), nystagmus; rarely - orofacial dyskinesia, oculomotor disorders, speech disorders (eg, dysarthria), choreoathetosis, peripheral neuropathy, paresthesia, paresis; very rarely - taste disorders, malignant neuroleptic syndrome.

From the skin and its appendages: very often - allergic dermatitis, hives, which can be very pronounced; sometimes - exfoliative dermatitis,erythroderma; rarely - systemic lupus erythematosus, itching; very rarely - Stevens-Johnson syndrome, toxic - epidermal necrolysis, photosensitivity reactions, multiform and erythema nodosum, skin pigmentation disorders, purpura, acne, sweating, hair loss, acute generalized exenthematous pustulosis. It reported rare cases of hirsutism, but the causal relationship of this complication of drug-remains unclear.

On the part of the hematopoiesis system: very often - leukopenia; often - thrombocytopenia, eosinophilia; rarely - leukocytosis, lymphadenopathy, deficiency of folic acid; very rarely - agranulocytosis, aplastic anemia, pancytopenia, anemia, true erythrocyte aplasia, megaloblastic anemia, variegate porphyria, late cutaneous porphyria, acute intermittent porphyria, reticulocytosis, and possibly hemolytic anemia.

During the administration of the drug, agranulocytosis and aplastic anemia can develop. However, due to the fact that these conditions occur very rarely, it is difficult to quantify the risk of their occurrence. It is known that the total risk of agranulocytosis in the general population not receiving treatment is 4.7 cases per million population per year, and aplastic anemia - 2.0 cases per million.of the population per year.

From the digestive system: very often - nausea, vomiting; often - dry mouth; infrequently - diarrhea, constipation; rarely - abdominal pain; very rarely - glossitis, stomatitis, pancreatitis.

FROMabout hepatobiliary system: very often - an increase in the level of gamma-glutamintransferase (due to the induction of this enzyme in the liver), which usually has no clinical significance; often - an increase in the level of alkaline phosphatase of the blood; sometimes - increased levels of transaminases; rarely - hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type, jaundice; very rarely - granulomatous hepatitis, liver failure.

Hypersensitivity reactions: rarely - multi-organ hypersensitivity of delayed type with fever, skin rashes, vasculitis, lymphadenopathy, signs resembling lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and altered liver function indicators (these manifestations occur in various combinations). Other organs may also be involved (eg, lungs, kidneys, pancreas, myocardium, large intestine); very rarely - aseptic meningitis with myoclonus and peripheral eosinophilia; anaphylactic reaction, angioedema.

If the above-mentioned hypersensitivity reactions occur, the drug should be discontinued.

Co cardiovascular system: rarely - violations of intracardiac conduction; increase or decrease in blood pressure; very rarely - bradycardia, fibrillation, AV block with syncope, circulatory collapse, congestive heart failure, worsening heart disease, thrombophlebitis, thromboembolism (e.g., pulmonary artery).

From the endocrine systemFrequently - edema, fluid retention, weight gain, hyponatremia and reduced blood osmolarity due to an effect similar to the action of antidiuretic hormone, which rarely leads to water intoxication (hyponatremia dilution), accompanied by lethargy, vomiting, headache, disorientation and neurologic violations; very rarely - an increase in the level of prolactin of the blood, accompanied or not accompanied by such manifestations as galactorrhea, gynecomastia; changes in the function of the thyroid gland - a decrease in the level of L-thyroxine (free thyroxine, thyroxine,triiodothyronine) and an increase in the thyroid-stimulating hormone level, which is usually not accompanied by clinical manifestations; metabolic disorders of bone tissue (decreased calcium and 25-hydroxy-colca-calcifer in the blood), which leads to osteomalacia / osteoporosis; increased cholesterol concentrations, including high-density lipoprotein cholesterol, and triglycerides.

From the urogenital systems: very rarely - interstitial nephritis, renal insufficiency, renal dysfunction (eg, albuminuria, hematuria, oliguria, urea / azotemia increase), frequent urination, urinary retention, sexual function / impotence disorders, spermatogenesis disorders (decrease in the number of spermatozoa and their mobility) .

From the sense organs: very rarely - a violation of taste, clouding of the lens, conjunctivitis, increased intraocular pressure; hearing disorders, incl. noise in the ears, hyperacusia, hypoacusia, changes in perception of the height of sound.

From the musculoskeletal system: rarely - muscle weakness, very rarely - arthralgia, muscle pain or cramps.

From the respiratory system: very rarely - reactions hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.

Change in the results of laboratory studies: very rarely - hypogammaglobulinemia.

Overdose:

Overdose is usually manifested by symptoms from the central nervous system, cardiovascular and respiratory systems.

In case of overdose, the following are possible Symptoms and complaints:

central nervous system: depression of CNS functions; impairment of consciousness, disorientation, drowsiness, agitation, hallucinations, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, hyperreflexia (at the beginning), hyporeflexia (later); convulsions, psychomotor disorders, myoclonus, hypothermia, mydriasis.

Respiratory system: respiratory depression, pulmonary edema.

The cardiovascular system: tachycardia, decrease and increase of arterial pressure, conduction disorders with QRS complex expansion; heart failure and fainting caused by cardiac arrest.

Gastrointestinal tract: vomiting, delayed evacuation of food from the stomach, decreased motility of the colon.

urinary system: retention of urine,oliguria or anuria; fluid retention; water intoxication (hyponatremia of dilution), caused by the effect of carbamazepine, similar to the action of antidiuretic hormone.

Changes in laboratory indicators: hyponatremia, metabolic acidosis is possible, hyperglycaemia is possible, increased activity of the muscle fraction of creatine phosphokinase.

Treatment

There is no specific antidote.

Initially, treatment should be based on the clinical status of patients; hospitalization is indicated.

The concentration of carbamazepine in the plasma is determined to confirm the poisoning of this agent and to assess the degree of overdose.

Evacuation of the stomach contents, gastric lavage, the use of activated charcoal are carried out. Late evacuation of gastric contents can lead to delayed absorption and re-emergence of symptoms of intoxication during recovery. Symptomatic supportive treatment is used in the intensive care unit, monitoring of heart functions, careful correction of water-electrolyte balance disorders.

Special Recommendations

With the development of arterial hypotension, iv administration of dopamine or dobutamine is indicated; when heart rhythm disturbances develop, treatment is selected individually; with the development of seizures - the introduction of benzodiazepines, for example, diazepam or other anticonvulsants, such as phenobarbital (with caution due to increased respiratory depression) or paraldehyde; with the development of hyponatremia (water intoxication) - restriction of fluid administration and careful intravenous injection of 0.9 % solution of sodium chloride, which can help prevent the development of brain damage. It is recommended to carry out hemosorption on carbon sorbents. Inefficiency of forced / diuresis, hemodialysis and peritoneal dialysis was reported. It is possible to re-increase the symptoms of overdose on the 2nd and 3rd day after its onset, which is due to the slow absorption of carbamazepine.

Interaction:

Cytochrome P4503A4 (CYP3A4) is the main enzyme providing formation of carbamazepine-10,11-epoxide (active metabolite). Simultaneous use of an inhibitor of the isoenzyme CYP3A4 with the preparation can lead to an increase in the concentration of carbamazepine in the plasma, which, in turn, can cause side reactions.Simultaneous use of inducers of the CYP3A4 isoenzyme may lead to an acceleration of the metabolism of carbamazepine and, thus, to a possible decrease in its concentration in the plasma and, consequently, to a possible decrease in the severity of the therapeutic effect of the drug. The cancellation of simultaneously taken inducers of the isoenzyme CYP3A4 can reduce the rate of biotransformation of carbamazepine, and, as a result, lead to an increase in the concentration of carbamazepine in the blood plasma.

Carbamazepine is a strong inducer of CYP3A4 and enzyme hepatic systems of the first and second phases and, when used simultaneously with drugs metabolized by CYP3A4, can cause induction of metabolism and a decrease in their concentration in the plasma.

Since the conversion of carbamazepine-10,11-epoxide to carbamazepine-10,11-trans-diol takes place with the microsomal enzyme of epoxide hydrolase, the use of carbamazepine along with epoxide hydrolase inhibitors can lead to an increase in the plasma concentration of carbamazepine-10,11-epoxide.

Premedies that can increase the concentration of carbamazepine in blood plasma: dextropropoxyphene, ibuprofen, danazol, macrolide antibiotics (for example, erythromycin, troleandomycin, josamycin, clarithromycin); fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine, styipentol, vigabatrin, azoles (for example, itraconazole, ketoconazole, fluconazole, voriconazole), loratadine, terfenadine, olanzapine, isoniazid, viral protease inhibitors for the treatment of HIV infection (eg, ritonavir), acetazolamide, verapamil, diltiazem, omeprazole, oxybutynin, dantrolene, ticlopidine, nicotinamide (in adults, only in high doses), it is possible - cimetidine, desipramine.

Since an increase in the level of carbamazepine in the blood plasma can lead to side effects (for example, dizziness, drowsiness, ataxia, diplopia), in these situations, the dose of the drug should be corrected and / or the carbamazepine concentration in the blood plasma determined regularly.

Drugs that can increase the concentration of carbamazepine-10,11-epoxide in the blood plasma: loxapine, quetiapine, primidon, progabide, valproic acid, valnoktamide and valpromid.

Since an increase in the level of carbamazepine-10,11-epoxide in blood plasma can lead to the occurrence of adverse reactions (eg, dizziness, drowsiness, ataxia, diplopia),in these situations, the dose of Zeptol should be corrected and / or the carbamazepine-10,11-epoxide concentration in the blood plasma measured regularly.

Drugs that can reduce the concentration of carbamazepine in blood plasma: felbamate, metsuximide, oxcarbazepine, phenobarbital, fensuximide, phenytoin and fosphenytoin, primidon, theophylline, aminophylline, isotretinoin, rifampicin, cisplatin or doxorubicin, herbal preparations containing Hypericum perforatum (Hypericum perforatum), and although the data are partially contradictory, possibly also clonazepam. With simultaneous application with the above drugs may be required; Correction of the dose of carbamazepine.

The effect of carbamazepine on the plasma concentration of drugs used as concomitant therapy

When combined with carbamazepine, a decrease in plasma concentration, a decrease or even a complete cessation of action of certain drugs is possible.

When used simultaneously with carbamazepine, you may need to adjust the doses of the following drugs: methadone, paracetamol, phenazone (antipyrine), tramadol, doxycycline, oral anticoagulants (warfarin, fenprokumone, dicoumarol and acenocoumarol), bupropion, citalopram, trazodone, tricyclic antidepressants (imipramine, amitriptyline, nortriptyline, clomipramine), clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidon, tiagabine, topiramate, valproic acid, zonisamide, itraconazole, praziquantel, imatinib, clozapine, haloperidol, bromperidol, olanzapine, quetiapine, risperidone, ziprasidone, used in the therapy of HIV infection (indinavir, ritonavir, saquinavir), alprazolam, midazolam, theophylline, calcium channel blockers of the dihydropyridine group (eg, felodipine), digoxin, oral contraceptive means (alternative methods of contraception are necessary), glucocorticosteroids (for example, prednisolone, dexamethosone), ciclosporin, everolimus; levothyroxine, preparations containing estrogens and / orprogesterone.

It has been reported that in patients receiving carbamazepine phenytoin plasma levels may either rise or fall, and mephenytoin level - increase (in rare cases).

Combinations that should be taken into account

In the appointment of carbamazepine together with levetiracetam in some cases, increased toxic effects of carbamazepine.

There are reports of increased hepatotoxicity caused by isoniazid, when it was used concomitantly with carbamazepine.

The combined use of carbamazepine and lithium or metoclopramide, as well as carbamazepine and neuroleptics (haloperidol, thioridazine) may lead to an increase in the incidence of unwanted neurologic reactions (in the case of the latter combination, even with therapeutic concentrations of active substances in the blood plasma.

The simultaneous use of carbamazepine with certain diuretic drugs (hydrochlorothiazide, furosemide) can lead to hyponatremia, accompanied by clinical manifestations.

Carbamazepine may exhibit antagonism to the action of nondepolarizing muscle relaxants (for example, pancuronium bromide). If such combinations of drugs are used, it may be necessary to increase the dose of these muscle relaxants; careful monitoring of patients should be carried out, as possible a faster, than expected, cessation of muscle relaxants.

Reported the occurrence of bleeding in women between menstruation in cases when oral contraceptives were used simultaneously. The drug may reduce the therapeutic effect of oral contraceptive preparations due to the induction of microsomal enzymes.

Carbamazepine, as well as other psychotropic drugs, can reduce the tolerance of alcohol. In this regard, the patient is recommended to abandon the use of alcohol.

Joint reception with grapefruit juice can increase the level of carbamazepine in plasma.

Special instructions:

The drug is usually ineffective in absences (petit mal) and myoclonic seizures. The drug should be used only on condition that regular medical supervision is provided.

During the application of the drug at different frequencies, there is a transient or persistent decrease in the number of platelets or leukocytes. However, in most cases, these phenomena are transient and usually do not precede the onset of aplastic anemia or agranulocytosis.

Before starting treatment, and also periodically during the treatment, clinical blood tests should be performed, including counting the number of platelets and, possibly, reticulocytes, as well as determining the concentration of iron in the blood serum.

It is necessary to inform patients about the early signs of toxicity inherent in probable hematologic disorders, as well as symptoms from the skin and liver. The patient is informed of the need to consult a doctor immediately if there are undesirable reactions such as fever, sore throat, rash, oral ulcers, an unreasonable occurrence of hemorrhages, haemorrhages in the form of petechiae or purpura.

With the use of carbamazepine, very severe dermatological reactions were very rare, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome). With the development of severe (in some cases life-threatening patient) skin reactions, the patient should be hospitalized in a hospital. In most cases, Stevens-Johnson syndrome and Lyell's syndrome developed during the first months of therapy with the drug.

According to a retrospective analysis of the use of the drug in Chinese patients, there is a correlation between the frequency of severe dermatological reactions and the presence of the HLA-B * 1502 human leukocyte antigen (HLA) gene in the patient's genome.

When carbamazepine was used in patients in the countries of the Asian region (Taiwan, Malaysia, Philippines), where there was a high prevalence of the HLA-B * 1502 allele, there was an increase in the frequency of development (from the "very rare" to "rarely") syndrome of Stevens-Johnson syndrome. The frequency of distribution of the HLA-B * 1502 allele is more than 15% in the Philippines and among some population groups in Malaysia. The frequency of distribution of the HLA-BM502 allele in Korea and India is 2% and 6%, respectively.

The prevalence of this allele in Caucasians, Negroid races, Latinos, Indians and Japanese is insignificant.

When prescribing carbamazepine, it is recommended that carriers of the HLA-B * 1502 allele (for example, Chinese nationals) be genotyped according to this allele. Prescribe the drug carriers of this allele should be only if the benefit of therapy exceeds the possible risk. In the face of the Caucasoid, Negroid and Americanic races, genotyping along the allele HLA-B*1502 is not necessary before prescribing carbamazepine.

Patients who are already receiving carbamazepine therapy are not recommended to carry out genotyping on this allele,because severe skin reactions in most cases were observed in the first months of application (regardless of the presence HLA-B* 1502 alleles). However, the results of genotyping by allele HLA-B*1502 should not affect the degree of control over the patient's condition and the doctor's vigilance in relation to severe skin reactions. The development of Stevens-Johnson and Lyell syndromes is possible in patients with a negative allele H-LAIn * 1502. Also in many cases, people of Chinese nationality, positive for the allele HLA-B*1502, when Carbamazepine was used, there was no development of Stevens-Johnson and Lyell syndromes.

The influence of other factors, such as the dose of anticonvulsant drugs, patient compliance, simultaneous therapy with other drugs, concomitant diseases or the level of control of dermatological reactions, the incidence and prevalence of severe skin reactions has not been established.

Slightly expressed skin reactions, for example, isolated macular or maculopapular exanthema, in most cases are transient and non-severe, usually occur for several days or weeks with continued treatment or after a reduction in the dose of the drug.Nevertheless, since differential diagnostics between early manifestations of severe skin reactions and mild transient skin rashes can be difficult, with the development of any skin reactions the patient should be under the supervision of a doctor (in order to timely stop therapy with the drug in case of deterioration of the patient's condition).

The relationship between the presence of the HLA-A * 3101 allele in the genome and the development of non-severe skin reactions (such as hypersensitivity syndrome, isolated macular or maculopapular exanthema) has not been established.

With the development of hypersensitivity to carbamazepine, patients can be observed as separate lesions of the skin, liver, blood and lymphatic systems or other organs, and their combination, which should be considered as a systemic reaction.

Patients with known hypersensitivity to carbamazepine should be informed about the possibility of 25-30% of cases of development of hypersensitivity reactions to oxcarbazepine.

Cross-reactivity hypersensitivity is also found between carbamazepine and phenytoin.

Before starting treatment with the drug and periodically during therapy, a general urine and urea test in the blood is recommended.

Before the appointment of carbamazepine and in the process of treatment, it is necessary to study the liver function, especially in patients whose history includes information on liver diseases, as well as in elderly patients. In case of strengthening of already existing violations of the liver function or with the appearance of active liver disease Carbamazepine should be immediately canceled.

The drug has a weak m-cholinoblocking activity. Therefore, in the case of using the drug in patients with increased intraocular pressure, constant monitoring of this indicator is necessary.

To date, individual reports of violations of male fertility and / or violations of spermatogenesis have been recorded. However, the causal relationship of these disorders with taking the drug has not been proven to date.

The drug may reduce the effectiveness of medications containing estrogens and / or progesterone, therefore women of childbearing age should be treated with alternative methods of protection from pregnancy during treatment with the drug.

Although the relationship between the dose of the drug, the concentration of carbamazepine in the blood plasma, its clinical efficacy or tolerability is very low, nevertheless, a regular determination of the carbamazepine concentration may be appropriate in the following situations: with a sharp increase in the frequency of seizures, in order to check whether the patient the drug is properly administered; during pregnancy; when treating children or adolescents; with suspected drug absorption abnormalities; if there is a suspicion of the development of toxic reactions in the event that the patient takes several medicines.

A sudden discontinuation of the drug may trigger epileptic seizures. If it is necessary to cancel the drug in a patient with epilepsy, the transition to another antiepileptic agent should be done under the cover of the drug shown in such cases (for example, diazepam administered intravenously or rectally or phenytoin administered intravenously).

Prior to the appointment of the drug, MAO inhibitors should be withdrawn at least 2 weeks or, if the clinical situation permits, even for a longer period.

In patients receiving antiepileptic drugs, there is an increased risk of suicidal behavior, including thoughts of suicide. In this regard, the patient's condition should be carefully monitored in order to timely detect the progression of depression, suicidal behavior, other changes in mood or unusual behavior of the patient.

Effect on the ability to drive transp. cf. and fur:

Ability of the patient receiving Carbamazepine, to a rapid reaction, especially at the beginning of therapy or during the period of dose selection, can be disrupted by the occurrence of dizziness and drowsiness. Therefore, when managing vehicles and working with mechanisms, the patient should be cautious.

Form release / dosage:

Tablets of 200 mg.

Packaging:

10 tablets per contour cell pack.

For 20 or 50 tablets in a can of light-protective glass or a can of polymeric or in a bottle a polymer or imported plastic bottle.

Each jar or bottle, 2 or 5 contour squares, together with instructions for use, is placed in a pack of cardboard.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LS-002649

Date of registration:26.09.2011

Expiration Date:Unlimited

The owner of the registration certificate:NORTH STAR, CJSC NORTH STAR, CJSC Russia

Manufacturer: & nbsp

NORTH STAR, CJSC Russia

Representation: & nbspNORTH STAR CJSC NORTH STAR CJSC Russia

Information update date: & nbsp07.12.2017

Illustrated instructions

Instructions

Carbamazepine (Carbamazepine)